Cancer cells with stemness characteristics effectively escape the recognition and killing of immune-active cells, such as T cells, which has been considered as the root cause of cancer recurrence and metastasis. To sensitize cancer immunotherapy, we have developed salinomycin-repurposed endoplasmic reticulum (ER) stress nanoinducers (DTSS NPs) to synergistically suppress cancer cell stemness. Salinomycin, as a polyether antibiotic demonstrating robust cytotoxicity against tumor stem cell, is co-assembled with thymopentin (TP5) and ER-targeted phototherapeutic agent s-780, and tailored with DSPE-PEG-biotin to obtain DTSS NPs. This nanoplatform not only improves the bioavailability of TP5 and salinomycin, but also ensures controlled drug release and reduces the side effects of therapeutic agents. Moreover, the hyperpyrexia and ROS produced by s-780 further induced ER stress, which downregulates PD-L1 expression and activates the cGAS-STING pathway, while TP5 significantly promotes the proliferation and differentiation of T lymphocytes, resulting in the augment of the anti-tumor immunity. Importantly, salomycin synergistically boosted s-780-mediated ER stress to effectively inhibit the stemness of cancer cells, thereby enhancing the responsiveness of cancer cells to T cells. As expected, DTSS NPs activate systemic immunity and suppress cancer metastasis and recurrence, providing promising solutions for sensitizing cancer immunotherapy by inhibiting cancer cell stemness.Copyright © 2025 Elsevier Ltd. All rights reserved.